title: FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors.
abstract: The purpose of this work--the first of its kind--was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand (18)F-fluorodeoxyglucose and positron emission tomography ((18)FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5 mg/kg) or CI-994 (5 mg/kg), (18)FDG-PET experiments (n=11-12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2-17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that (18)FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Schroeder
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Chonde
authors.forename: Misha M
authors.initials: MM
authors.lastname: Riley
authors.forename: Christian K
authors.initials: CK
authors.lastname: Moseley
authors.forename: Michael L
authors.initials: ML
authors.lastname: Granda
authors.forename: Colin M
authors.initials: CM
authors.lastname: Wilson
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gale
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
mesh_terms: D000818:Animals; D001549:Benzamides; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D059906:Neuroimaging; D010655:Phenylenediamines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; D019788:Fluorodeoxyglucose F18; D005947:Glucose; C081895:tacedinaline
keywords: Acetylation; Chromatin; Epigenetic; Metabolism; Necuroimaging; Rat